The bleomycins are a family of glycopeptides derived antitumor antibiotics originally isolated from Streptomyces verticillus. Some of the bleomycins are used clinically for the treatment of squamous cell carcinomas and malignant lymphomas. While numerous studies of bleomycin have been carried out in the past few decades, few of these have addressed two remarkable properties of bleomycin, namely its tumor seeking properties and the way in which it targets its DNA substrates under physiological conditions. The present project is based on new strategies which provide (i) a facile method for monitoring the tumor seeking properties of bleomycin and (ii) an approach for identifying high affinity nucleic acid targets for bleomycin. Goals of the project include identification of the structural elements in bleomycin that are required for tumor targeting, as well as the cellular constituents that are recognized. Also proposed is the identification of DNA motifs that are bound and cleaved with exceptionally high efficiency by bleomycin.

Public Health Relevance

The bleomycins are used clinically for the treatment of certain tumors that occur in soft tissues. The studies proposed here will facilitate an understanding of the way that this drug targets tumors, and binds to and degrades the nucleic acids in tumor tissue. As such, these studies will enable the preparation of bleomycins with improved properties.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140471-03
Application #
8204865
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Misra, Raj N
Project Start
2010-01-18
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$306,945
Indirect Cost
$105,670
Name
Arizona State University-Tempe Campus
Department
Miscellaneous
Type
Organized Research Units
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Roy, Basab; Tang, Chenhong; Alam, Mohammad P et al. (2014) DNA methylation reduces binding and cleavage by bleomycin. Biochemistry 53:6103-12
Roy, Basab; Hecht, Sidney M (2014) Hairpin DNA sequences bound strongly by bleomycin exhibit enhanced double-strand cleavage. J Am Chem Soc 136:4382-93
Tang, Chenhong; Paul, Ananya; Alam, Mohammad P et al. (2014) A short DNA sequence confers strong bleomycin binding to hairpin DNAs. J Am Chem Soc 136:13715-26
Madathil, Manikandadas M; Bhattacharya, Chandrabali; Yu, Zhiqiang et al. (2014) Modified bleomycin disaccharides exhibiting improved tumor cell targeting. Biochemistry 53:6800-10
Schroeder, Benjamin R; Ghare, M Imran; Bhattacharya, Chandrabali et al. (2014) The disaccharide moiety of bleomycin facilitates uptake by cancer cells. J Am Chem Soc 136:13641-56
Bhattacharya, Chandrabali; Yu, Zhiqiang; Rishel, Michael J et al. (2014) The carbamoylmannose moiety of bleomycin mediates selective tumor cell targeting. Biochemistry 53:3264-6
Segerman, Zachary J; Roy, Basab; Hecht, Sidney M (2013) Characterization of bleomycin-mediated cleavage of a hairpin DNA library. Biochemistry 52:5315-27
Yu, Zhiqiang; Schmaltz, Ryan M; Bozeman, Trevor C et al. (2013) Selective tumor cell targeting by the disaccharide moiety of bleomycin. J Am Chem Soc 135:2883-6
Giroux, Rachel A; Hecht, Sidney M (2010) Characterization of bleomycin cleavage sites in strongly bound hairpin DNAs. J Am Chem Soc 132:16987-96